Rahul Sreekumar MRC SIP1 induced epithelial to mesenchymal transition (EMT) promotes metastasis and chemoresistance in colorectal cancer

Bowel cancer is the second most common cause of cancer related death in the UK, and it is spread of the cancer (Metastasis), that is the main cause of this high death rate. Unfortunately, up to a third of patients present with evidence of cancer spread at initial presentation, and up to half of all cases subsequently experience recurrence of disease from previously undetected occult metastases after their operation. While there has been some advances in the management of patients with recurrent bowel cancer, the vast majority of patients in this position are incurable and sadly can expect a median life expectancy of less than two years, even with the latest chemotherapy drugs. Emerging evidence in recent years has highlighted the role of certain key molecules that normally regulate the development of embryos, to be abnormally expressed in cancer cells, making them not only more likely to invade and spread, but also to become resistant to chemotherapeutic drugs. Little is known about the expression or role of one of these key proteins, known as SIP1, in bowel cancer. Preliminary work conducted by me so far has highlighted that SIP1, when present in bowel tumors, results in an increased likelihood of cancer recurrence, reduced patient survival, and increased resistance against commonly used chemotherapeutic drugs in the treatment of bowel cancer. Consequently, SIP1 may be a helpful biomarker for clinically useful outcome measures in patients with bowel cancer. I have conducted further work to try to explain the mechanism behind this observation. Our results suggested that one potential explanation for the resistance to chemotherapy observed is due to the increased ability of cancer cells, containing SIP1, to repair the damage brought about by chemotherapy, and thereby avoid cancer cell death. Based on the above novel observations, the primary goals of my research proposal are two fold. The first aim of my study is to better understand the underlying mechanisms by which bowel cancer cells increase their capacity to repair cellular injury through the actions of SIP1. This work will not only enhance our understanding of basic biological processes in cells, but it may also enable the creation of targeted drugs to inhibit these repair systems and subsequently increase the sensitivity of cancer cells to chemotherapy drugs, potentially impacting the lives of many sufferers. This work will involve the use of cells grown in culture, but also studies in a carefully calculated number of mice to ensure that my findings are as closely related to physiological circumstances as possible, and therefore more likely to take the next step and enter studies in man. As a clinician, my goal is to translate new laboratory findings into patient care, consequently my second aim is to more fully develop and test the use of SIP1 as a biomarker that could help in the personalisation of the management of bowel cancer by assisting in risk prediction for cancer recurrence and potentially chemotherapy response. Validating my promising results on a larger and independent group of patients is an essential per-requisite for translating these findings into real-time patient management. For that reason, I have teamed up with colleagues in Italy and we aim to test the generality of my findings in an independent patient group from their unit. If successful, my research will provide significant insight into mechanisms by which cancer spreads and gains resistance to current drug therapies, and may facilitate better clinical management and drug discovery in future years.